PATHOPHYSIOLOGY OF CHRONIC CEREBRAL VASOSPASM

慢性脑血管痉挛的病理生理学

• 批准号: 2891721
• 负责人: BRYCE K WEIR
• 金额: $ 43.85万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2891721
• 关键词: Primates; adenine nucleotides; adenosine triphosphate; calcium flux; cerebral aneurysm; cerebral hemorrhage; cerebrospinal fluid; clinical research; disease /disorder model; endothelin; erythrocytes; hemoglobin; human subject; laboratory rat; pathologic process; polymerase chain reaction; protein biosynthesis; tissue /cell culture; vascular endothelium; vascular smooth muscle; vasodilators; vasospasm

Rupture of an intracranial aneurysm, causing subarachnoid hemorrhage (SAH), afflicts about 30,000 North Americans per year. An important cause of stroke and death in patients with ruptured aneurysms is cerebral vasospasm which is narrowing of the major cerebral arteries developing from 4 to 14 days after aneurysm rupture. Vasospasm causes morbidity and mortality in about 15% of patients with SAH although angiograms taken during the time of vasospasm will disclose its presence in about two-thirds of cases. Treatment of vasospasm, that includes calcium-channel antagonists, hemodynamic therapy and tissue plasminogen activator, accounts for some of the discrepancy between the number of patients with vasospasm seen angiographically compared to those who develop stroke from it. The long-term objectives of our laboratory are (1) to determine the compound(s) in subarachnoid blood that cause vasospasm, (2) to determine the mechanisms by which they do so, and (3) to develop effective treatments for vasospasm. The specific aims of this grant are (1) to determine how the time course and degree of vasospasm in monkeys depends on subarachnoid blood and to analyze the blood for spasmogens, (2) to determine the component(s) of erythrocytes that cause vasospasm in rats, (3) to characterize the vasoactive compound in cerebrospinal fluid (CSF) and subarachnoid blood removed from patients with SAH, (4) to determine whether adenosine triphosphate (ATP) and pure hemoglobin can cause vasospasm in monkeys, (5) to determine the concentrations and time course of changes-in CSF levels of adenine nucleotides and hemoglobins in humans after SAH, (6) to determine the effects of P2-purinoceptor antagonists against vasospasm in monkeys, (7) to determine if synthesis of endothelin (ET) and ET receptor messenger ribonucleic acids (mRNAs) and secretion of ET and ET receptor proteins are increased in cultured cerebral smooth muscle and endothelial cells exposed to erythrocyte hemolysate or purified hemoglobin, (8) to determine the time course of changes in ET and ET receptor mRNAs and proteins following SAH in rats and (9) to determine the effects of an ET antagonist on vasospasm in monkeys.

颅内动脉瘤破裂，导致蛛网膜下腔出血 (SAH)每年约有30，000名北美人受到影响。一个重要 动脉瘤破裂患者中风和死亡的原因是 脑血管痉挛，即主要脑动脉狭窄 发生于动脉瘤破裂后4 ~ 14天。血管痉挛原因 约15%的SAH患者的发病率和死亡率， 在血管痉挛期间拍摄的血管造影片将显示其 在约三分之二的病例中。血管痉挛的治疗， 包括钙通道拮抗剂、血液动力学治疗和组织 纤溶酶原激活剂，解释了一些差异， 血管造影观察到血管痉挛的患者数量与 我们的长期目标是， 实验室是（1）确定蛛网膜下腔血液中的化合物 （2）确定它们引起血管痉挛的机制， 因此，（3）开发有效的血管痉挛治疗方法。具体 该补助金的目的是（1）确定时间进程和程度 猴子的血管痉挛依赖于蛛网膜下腔的血液， 血液中的痉挛原，（2）确定成分 红细胞引起大鼠血管痉挛，（3）表征 脑脊液和蛛网膜下腔血中的血管活性化合物 从SAH患者中取出，（4）以确定腺苷是否 三磷酸盐（ATP）和纯血红蛋白可引起猴子的血管痉挛， (5)以确定CSF中的浓度和变化的时间过程， SAH后人类的腺嘌呤核苷酸和血红蛋白水平，（6） 为了确定P2-嘌呤受体拮抗剂对 猴血管痉挛;（7）测定内皮素（ET）的合成 和ET受体信使核糖核酸（mRNA）和ET的分泌 培养的脑平滑肌细胞ET受体蛋白表达增加， 暴露于红细胞溶血产物的肌肉和内皮细胞，或 纯化血红蛋白，（8）以确定ET变化的时间过程 大鼠SAH后ET受体mRNA和蛋白的表达; 确定内皮素拮抗剂对猴子血管痉挛的影响。